Title: Pharmacogenetics of mood stabilizing drugs in the genetic model organism Drosophila melanogaster
Other Titles: Farmacogenetica van stemmingsstabiliserende geneesmiddelen in het genetisch model organisme Drosophila melanogaster
Authors: Herteleer, Liesbet; M0117869
Issue Date: 3-Jul-2012
Abstract: Behavioral neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are severe and chronic mental illnesses that are difficult to diagnose due to changing diagnostic criteria, overlap of symptoms among psychiatric disorders and the co-occurrence with other disorders. Moreover, they are an increasing problem in society and are accompanied by a whole range of other issues. A prominent problem in the clinic for instance is the wide variety in responses upon mood stabilizer treatment with only approximately half of the treated patients with bipolar disorder are considered responders. Furthermore, although these drugs have been used for decades, until today it is not clear which affected molecules or pathways in particular are responsible for their beneficial clinical effects. Also, studies searching for genetic polymorphisms associated with bipolar disorder and schizophrenia have proven difficult, even when using large patient samples, due to the complexity of variants involved in these disorders and the heterogeneity of the patient population. In this thesis we demonstrate that Drosophila melanogaster can be used successfully as a genetically tractable model to perform pharmacogenetic studies for psychiatric disorders.Firstly, we identify genetic factors that influence variation in drug response for mood stabilizing drugs, lithium and valproate, as measured by variation in aggressive behavior. By means of a simple behavioral assay we demonstrate that there are not only time-dependent differences in genetic factors that are affected by these two drugs, but that lithium and valproate are also different with respect to genetic markers associated with their effects. We also find significantly enriched functional categories within the genes that were identified as contributing to genotype by environment interaction for both drugs. Genes with functions in axonogenesis, neural development and differentiation and genes encoding ion channels, were relevant for variation of this behavior and therefore potentially valuable targets for validation in patients with bipolar disorder or schizophrenia. Secondly, we find differentially regulated transcripts upon treatment of cells with the two mood stabilizers. A key finding is that there is no overlap between lithium and valproate with respect to their effects on individual transcripts, notwithstanding their similar therapeutic effect and similar effect on neurons. However, we also find several pathways affected by both drugs, such as triacylglyceride synthesis, the Notch pathway and glycogen metabolism. Next, we identify transcripts whose expression is affected by both mood stabilizers in the cells and in Drosophila heads to then determine whether such transcripts are involved in adult behavior. We show that a high number of genes alter the startle-induced locomotion response, a simple model for sensorimotor gating, a process affected in several neuropsychiatric disorders. So, by making an overlap of genes whose transcription is differentially modulated upon lithium and VPA treatment of cells and the fruit fly¬ís nervous system, we found a high number of genes that are involved in the modulation of a behavioral response in a stimulus-induced arousal test. By means of two different approaches, we demonstrate the complexity and importantly the differences in the effects of the mood stabilizing drugs, lithium and valproate, at the transcript level. Moreover, our experiments and others can eventually lead to the identification of important biological pathways and key mechanisms in psychiatric disorders. Our data indicate that evidence from cell and animal models in combination with current knowledge in psychiatric genetics can provide more biological meaning and insight into different pathways and mechanisms that not only control variation of treatment response, but are also affected by mood stabilizer treatment and may be important in the etiology of bipolar disorder and schizophrenia. Thirdly, we determine whether human homologs of Drosophila genes affected by mood stabilizing drugs and genes related to the networks in which they play an important role are implicated in psychiatric disorders. After analyzing these genes in patients with bipolar disorder, schizophrenia and control individuals, we find significant allelic associations with both bipolar disorder and schizophrenia. This approach of analyzing convergent genomic data proves to be very efficient for the identification of functional gene categories potentially important for the etiology of bipolar disorder and schizophrenia and may be very relevant to identify the most interesting mechanisms to target with new, innovative and disorder-modifying, therapeutic agents.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Department of Human Genetics - miscellaneous

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